Anxiety Disorders
Although traditional benzodiazepines (BZDs) and their congeners have been the drugs of choice for the relief of generalized anxiety for over 30 years, they have not been used in the treatment of panic disorders. Recently, it has been generally reported that the so-called "high potency" BZDs (alprazolam, clonazepam, bretazenil) can be differentiated from traditional BZD's in experiments which indicate the potential of a drug to be effective as an antipanic agent. Giusti et al., J. Pharmacol. Exper. Therapeutics 257:1062-68 (1991).
The Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DMS III) (1980), divides anxiety/neurosis into the following subtypes: generalized anxiety, panic disorders, and obsessive-compulsive disorders. Although numerous behavioral procedures are used successfully to predict the action of drugs on generalized anxiety, a comparable behavioral model for the study of drugs active on panic disorders and obsessive behaviors has been lacking. A simple behavioral test in rats that predicts the antipanic potency of drugs acting on GABA receptors has been developed. In this test, the acute punished suppression of the drinking paradigm in thirsty rats (Vogel test) was used to discriminate between diazepam, zolpidem, alpidem, and midazolam, which are low potency BZDs with anxiolytic properties, and alprazolam, clonazepam, and bretazenil, which are high potency BZDs effective in the treatment of panic disorders. The Vogel test, in its conflict paradigm, can be used in animals to ascertain the potential anxiolytic or anxiety producing properties of drugs. When the Vogel test is used in conjunction with pentylenetetrazole (PTZ) treatment it is called "proconflict test" and can be used to ascertain the antipanic potential of drugs PTZ has been used to decrease GABA.sub.A receptor function and therefore to make the Vogel test more sensitive to antipanic BZD drugs.
In man, subconvulsant doses of PTZ produce intense anxiety and sense of impending doom, a behavioral syndrome reminiscent of a panic attack. Thus, the Vogel test in both conflict and proconflict (PTZ-facilitated conflict) paradigms is used as an animal model to evaluate the GABA.sub.A receptor contribution to the action of drugs that decrease response suppression. When a series of BZDs and their congeners are evaluated in the proconflict paradigm, it is found that the potencies and efficacies of the antipanic BZDs alprazolam, clonazepam, and bretazenil surpassed those of the anxiolytic BZD ligands diazepam, zolpidem, alpidem, and midazolam.
Diazepam, midazolam, alpidem, and zolpidem antagonized the conflict and proconflict responses in a dose-dependent manner with similar potencies and efficacies, yielding anti-proconflict indexes close to 1. On the other hand, the 1,4-BZD clonazepam, the triazolo 1,4-BZD alprazolam, and the imidazo 1,4-BZD bretazenil also increased the threshold for the conflict behavior in a dose-dependent manner, but they were significantly more potent in antagonizing the proconflict effect elicited by PTZ. These drugs yielded anti-proconflict indexes close to 10. Because there was no correlation between the anti-proconflict index values and the doses of BZDs that elicited other behavioral responses, including the ability to prevent PTZ-induced convulsions, a higher anti-proconflict index is predictive of an antipanic action for a special class of BZDs.